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Molecular and Cellular Biology, November 2005, p. 10060-10070, Vol. 25, No. 22
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.22.10060-10070.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Insights into the Role of Histone H3 and Histone H4 Core Modifiable Residues in Saccharomyces cerevisiae{dagger}

Edel M. Hyland,1 Michael S. Cosgrove,2,{ddagger} Henrik Molina,3 Dongxia Wang,4,§ Akhilesh Pandey,3 Robert J. Cottee,4 and Jef D. Boeke1*

High Throughput Biology Center,1 Department of Biophysics and Biophysical Chemistry,2 Mass Spectrometry Facility, Department of Biological Chemistry,3 Middle Atlantic Mass Spectrometry Laboratory, Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland4

Received 5 May 2005/ Returned for modification 6 June 2005/ Accepted 22 August 2005

The biological significance of recently described modifiable residues in the globular core of the bovine nucleosome remains elusive. We have mapped these modification sites onto the Saccharomyces cerevisiae histones and used a genetic approach to probe their potential roles both in heterochromatic regions of the genome and in the DNA repair response. By mutating these residues to mimic their modified and unmodified states, we have generated a total of 39 alleles affecting 14 residues in histones H3 and H4. Remarkably, despite the apparent evolutionary pressure to conserve these near-invariant histone amino acid sequences, the vast majority of mutant alleles are viable. However, a subset of these variant proteins elicit an effect on transcriptional silencing both at the ribosomal DNA locus and at telomeres, suggesting that posttranslational modification(s) at these sites regulates formation and/or maintenance of heterochromatin. Furthermore, we provide direct mass spectrometry evidence for the existence of histone H3 K56 acetylation in yeast. We also show that substitutions at histone H4 K91, K59, S47, and R92 and histone H3 K56 and K115 lead to hypersensitivity to DNA-damaging agents, linking the significance of the chemical identity of these modifiable residues to DNA metabolism. Finally, we allude to the possible molecular mechanisms underlying the effects of these modifications.

* Corresponding author. Mailing address: 339 Broadway Research Building, 733 North Broadway, Baltimore MD 21205. Phone: (410) 955-0398. Fax: (410) 502-1872. E-mail: jboeke{at}jhmi.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Department of Biology, Syracuse University, Syracuse, N.Y.

§ Present address: Biotechnology Core Facility, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333.

Molecular and Cellular Biology, November 2005, p. 10060-10070, Vol. 25, No. 22
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.22.10060-10070.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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